Abstract 13937: Human Microvascular Dysfunction Induced by Glucose and VLDL Lipolysis Products and Protective Effect of Exenatide in Hyperglycemia
Type 2 diabetes mellitus and insulin resistance (T2DM/IR) are associated with microvascular complications in part due to direct toxic effects of hyperglycemia (HG) and free fatty acids on the vasculature; however, the lack of a viable human tissue model constrains verification of direct effects of these metabolic insults on arterioles. We hypothesized that HG and free fatty acids/VLDL lipolysis products (FFA/VLDL) induce endothelial and non-endothelial dysfunction in adipose arterioles and that GLP-1 receptor agonist exenatide has direct vasoprotective action against HG.
Methods: Ex-vivo arterioles were isolated from subcutaneous adipose tissue in normal subjects (40-65 years old), cannulated and pressurized. Dilator response to acetylcholine (endothelium) and papaverine (non-endothelium) were measured following exposure to 2 hours of HG (33 mM) ± exenatide (10 nM) or FFA/VLDL (150-300 µM FFA, derived from VLDL + 0.25 units lipoprotein lipase). Human aortic endothelial cells (HAEC) were exposed to 4 hours of HG±exenatide at similar concentrations and NO head gas was measured with NO analyzer.
Results: See figure (V=baseline/vehicle control)
Conclusions: We show for the first time that free fatty acids/VLDL lipolysis products and HG directly impair endothelial and non-endothelial function of human adipose arterioles, and that GLP-1 receptor agonist exenatide is directly vasoprotective against HG-induced microvascular dysfunction, likely related to enhancing NO bioavailability. Use of ex-vivo human arterioles allows investigation of direct vascular effects of metabolic risk factors. Our novel findings suggest that GLP-1 receptor agonists may offer a new therapeutic paradigm for preventing microvascular complications in T2DM/IR.
- © 2011 by American Heart Association, Inc.